Dear Sir,

We have read with great interest the recent review article by Epstein, entitled “Pros, cons, and costs of INFUSE in spinal surgery”.[ 6 ] We would like to congratulate the author on the thorough review of the current findings on the controversial topic of the “off-label” use of bone morphogenetic protein INFUSE™ [recombinant human bone morphogenetic protein-2 (rhBMP-2); Medtronic, Memphis, TN, USA] in cervical, thoracic, and lumbar spine surgery.[ 6 ]

We would also like to commend the author for listing sexual dysfunction among the complications reported in conjunction with the application of INFUSE™ and the LT Cage™,[ 6 ] as it is a complication that has not been mentioned in this context until recently.[ 17 – 22 ] Sexual dysfunction, particularly retrograde ejaculation (RE), was so far encountered only after anterior lumbar interbody fusion (ALIF), a procedure in which the application of INFUSE was approved by the US Food and Drug Administration (FDA).[ 14 ] It has been described in the articles by Burkus et al.[ 2 ] and Sasso et al.,[ 13 ] and clearly stated as “a potential adverse event which may occur with spinal fusion surgery with the INFUSE™ Bone Graft/LT-CAGE™ Lumbar Tapered Fusion Device” in the FDA Device Approval Summary of Safety and Effectiveness Data.[ 14 ]

The underlying mechanism of the dysfunction is the inability of the internal vesical sphincter to contract during ejaculation, resulting in retrograde flow of semen to the urinary bladder.[ 13 ] As the muscle is innervated by the superior hypogastric plexus, i.e., a thin, retroperitoneal plexus of nerves overlying the lumbosacral junction, damage to the plexus during (or after) ALIF can denervate the bladder neck sphincter.

To the best of our knowledge, we were the first to point out the connection between sexual dysfunction and rhBMP-2 use in spinal surgery.[ 17 – 22 ] The authors of the studies[ 19 20 22 ] have categorically denied this causal relationship, although they did not provide any explanation for the appearance of the dysfunction, months after the surgical procedures (according to the FDA's reporting),[ 14 ] which is in concordance with current findings on late inflammatory reactions and/or pressure exerted by the ectopic bone on the superior hypogastric plexus.

Finally, by examining the articles cited by Epstein,[ 1 3 – 5 7 – 12 15 16 23 – 25 ] we did not find any mention of sexual dysfunction as a complication. Therefore, we would like to know what source the author referred to when stating sexual dysfunction as a complication of, if we understood correctly, “off-labeled” application of INFUSE™ in spinal surgery?

In the study I published in January in Surgical Neurology International entitled “Pros, Cons, and Costs of INFUSE in Spinal Surgery”, I reported that INFUSE and the LT Cage, were associated with sexual dysfunction.[ 26 ] I would like to clarify that I was referring to retrograde ejaculation alone.

The authors of this commentary further expanded upon the etiology and physiology of retrograde ejaculation which may occur when recombinant human bone morphogenetic protein-2 [rhBMP-2] [INFUSE: Medtronic, Memphis, TN USA] is utilized to perform anterior lumbar interbody fusions [ALIF] with the LT Lumbar Tapered Fusion Device.[ 27 – 29 ]

The authors go on to discuss the actual mechanism of retrograde ejaculation: the “inability of the internal vesical sphincter to contract during ejaculation, resulting in retrograde flow of semen to the urinary bladder”. Retrograde ejaculation occurs, therefore, secondary to interference with the superior hypogastric plexus, “a thin retroperitoneal plexus of nerves overlying the lumbosacral junction”. Trauma to this plexus, therefore, likely occurs during ALIF, resulting in "denervation of the bladder neck sphincter".

The authors of this commentary further note that other studies have failed to recognize the “causal relationship” between the ALIF and retrograde ejaculation. The failure to acknowledge this complication in multiple studies is even more disturbing as the retrograde ejaculation appears to directly follow ALIFs, often lasting for several postoperative months.

References

1. Balseiro S, Nottmeier EW. Vertebral osteolysis originating from subchondral cyst end plate defects in transforaminal lumbar interbody fusion using rhBMP-2. Report of two cases. Spine J. 2010. 10: e6-10

2. Burkus JK, Gornet MF, Dickman CA, Zdeblick TA. Anterior lumbar interbody fusion using rhBMP-2 with tapered interbody cages. J Spinal Disord Tech. 2002. 15: 337-49

3. Burkus JK, Transfeldt EE, Kitchel SH, Watkins RG, Balderston RA. Clinical and radiographic outcomes of anterior lumbar interbody fusion using recombinant human bone morphogenetic protein-2. Spine (Phila Pa 1976). 2002. 27: 2396-408

4. Carreon LY, Glassman SD, Brock DC, Dimar JR, Puno RM, Campbell MJ. Adverse events in patients re-exposed to bone morphogenetic protein for spine surgery. Spine (Phila Pa 1976). 2008. 33: 391-3

5. Deutsch H. High-dose bone morphogenetic protein-induced ectopic abdomen bone growth. Spine J. 2010. 10: e1-4

6. Epstein NE. Pros, cons, and costs of INFUSE in spinal surgery. Surg Neurol Int. 2011. 2: 10-

7. Glassman SD, Carreon LY, Campbell MJ, Johnson JR, Puno RM, Djurasovic M. The perioperative cost of Infuse bone graft in posterolateral lumbar spine fusion. Spine J. 2008. 8: 443-8

8. Glassman SD, Carreon LY, Djurasovic M, Campbell MJ, Puno RM, Johnson JR. RhBMP-2 versus iliac crest bone graft for lumbar spine fusion: A randomized, controlled trial in patients over sixty years of age. Spine (Phila Pa 1976). 2008. 33: 2843-9

9. Glassman SD, Howard J, Dimar J, Sweet A, Wilson G, Carreon L. Complications with rhBMP-2 in posterolateral spine fusion: A consecutive series of one thousand thirty-seven cases. Spine (Phila Pa 1976). 2010. p.

10. Mannion RJ, Nowitzke AM, Wood MJ. Promoting fusion in minimally invasive lumbar interbody stabilization with low-dose bone morphogenic protein-2-but what is the cost?. Spine J. 2010. p.

11. Mroz TE, Wang JC, Hashimoto R, Norvell DC. Complications related to osteobiologics use in spine surgery: A systematic review. Spine (Phila Pa 1976). 2010. 35: S86-104

12. Owens K, Glassman SD, Howard JM, Djurasovic M, Witten JL, Carreon LY. Perioperative complications with rhBMP-2 in transforaminal lumbar interbody fusion. Eur Spine J. 2011. 20: 612-7

13. Sasso RC, Burkus JK, LeHuec JC. Retrograde ejaculation after anterior lumbar interbody fusion: Transperitoneal versus retroperitoneal exposure. Spine (Phila Pa 1976). 2003. 28: 1023-6

14. Last Accessed on 2010 Feb 14. Available from: http://www.accessdata.fda.gov/cdrh_docs/pdf/P000058b.pdf .

15. Shahlaie K, Kim KD. Occipitocervical fusion using recombinant human bone morphogenetic protein-2: Adverse effects due to tissue swelling and seroma. Spine (Phila Pa 1976). 2008. 33: 2361-6

16. Shields LB, Raque GH, Glassman SD, Campbell M, Vitaz T, Harpring J. Adverse effects associated with high-dose recombinant human bone morphogenetic protein-2 use in anterior cervical spine fusion. Spine (Phila Pa 1976). 2006. 31: 542-7

17. Smoljanovic T, Bicanic G, Bojanic I. Re: Kleeman TJ, Ahn UM, Talbot-Kleeman A.Laparoscopic anterior lumbar interbody fusion with rhBMP-2: A prospective study of clinical and radiographic outcomes. Spine. 2001. 26: 2751-6

18. Smoljanovic T, Bojanic I, Re: Mroz TE, Wang JC, Hashimoto R, Norvell DC. Complications related to osteobiologics use in spine surgery: A systematic review. Spine (Phila Pa 1976). 2010. 35: S86-104

19. Smoljanovic T, Bojanic I, Cimic M, Re: Boden SD, Zdeblick TA, Sandhu HS. The use of rhBMP-2 in interbody fusion cages. Definitive evidence of osteoinduction in humans: A preliminary report. Spine (Phila Pa 1976). 2000. 25: 376-81

20. Smoljanovic T, Bojanic I, Rakovac M, Re: Sasso RC, Burkus JK, LeHuec JC. Retrograde ejaculation after anterior lumbar interbody fusion: Transperitoneal versus retroperitoneal exposure. Spine (Phila Pa 1976). 2003. 28: 1023-6

21. Smoljanovic T, Rakovac M, Bojanic I. Could chronic host inflammatory response be responsible for delayed onset of retrograde ejaculation after the labeled use of recombinant human bone morphogenetic protein-2?. Spine J. 2011. 11: 167-8

22. Smoljanovic T, Siric F, Bojanic I. Six-year outcomes of anterior lumbar interbody arthrodesis with use of interbody fusion cages and recombinant human bone morphogenetic protein-2. J Bone Joint Surg Am. 2010. 92: 2614-5

23. Stambough JL, Clouse EK, Stambough JB. Instrumented one and two level posterolateral fusions with recombinant human bone morphogenetic protein-2 and allograft: A computed tomography study. Spine (Phila Pa 1976). 2010. 35: 124-9

24. Wong DA, Kumar A, Jatana S, Ghiselli G, Wong K. Neurologic impairment from ectopic bone in the lumbar canal: A potential complication of off-label PLIF/TLIF use of bone morphogenetic protein-2 (BMP-2). Spine J. 2008. 8: 1011-8

25. Yaremchuk KL, Toma MS, Somers ML, Peterson E. Acute airway obstruction in cervical spinal procedures with bone morphogenetic proteins. Laryngoscope. 2010. 120: 1954-7

26. Epstein NE. Pros, cons, and costs of INFUSE in spinal surgery. Surg Neurol Int. 2011. 2: 10-

27. Sasso RC, Burkus JK, LeHuec JC. Retrograde ejaculation after anterior lumbar interbody fusion: Transperitoneal versus retroperitoneal exposure. Spine (Phila Pa 1976). 2003. 28: 1023-6

28. Smoljanovic T, Bojanic I, Rakovac M, Re: Sasso RC, Burkus JK, LeHuec JC. Retrograde ejaculation after anterior lumbar interbody fusion: transperitoneal versus retroperitoneal exposure. Spine (Phila Pa 1976). 2003. 28: 1023-6

29. Smoljanovic T, Rakovac M, Bojanic I. Could chronic host inflammatory response be responsible for delayed onset of retrograde ejaculation after the labeled use of recombinant human bone morphogenetic protein-2?. Spine J. 2011. 11: 167-8